T-cell immunity is central for the control of COVID-19, in particular in patients incapable to mount a humoral immune response. We previously reported on the favorable safety profile and efficacy in terms of induction of SARS-CoV-2-specific T-cell responses by CoVac-1, a peptide-based T-cell activator, composed of SARS-CoV-2 T-cell epitopes derived from various viral proteins, combined with the toll-like receptor 1/2 agonist XS151. We conducted a Phase I/II open-label trial recruiting 54 patients with congenital or acquired B-cell deficiency who received one single subcutaneous dose of CoVac-1. Immunogenicity until day 28 in terms of CoVac-1-induced T-cell responses was the primary endpoint; safety until day 56 was assessed as secondary endpoint. Neither serious nor grade 4 CoVac-1-related adverse events were observed. The expected local granuloma formation was observed in 94% of study subjects, whereas systemic reactogenicity was mostly mild or absent. SARS-CoV-2-specific Tcell responses were induced in 86% of the patients and directed to multiple CoVac-1 peptides, not affected by any current Omicron variants and mediated by multifunctional T-helper 1 CD4+ T cells. CoVac-1-induced T-cell responses exceeded spike-specific T-cell responses after vaccination with mRNA vaccines in B-cell deficient patients and also that of immunocompetent COVID-19 convalescents with and without seroconversion. CoVac-1 induces broad and potent T-cell responses in patients with Bcell/antibody deficiency independently of current variants of concern, with a favorable safety profile. Our data warrant advancement to a pivotal Phase II/III safety and efficacy evaluation.